Evolution and Mechanistic Insights of Immunometabolism in Metabolic Diseases and Infections

ABSTRACT

Immunometabolism, an emerging field exploring metabolic reprogramming and functional regulation in immune cells, offers a lens for understanding complex diseases. This review delineates core concepts, key signalling nodes—emphasising the mechanistic target of rapamycin (mTOR) as an integrator of metabolic and immune signals—research and intervention strategies across metabolic and infectious diseases. Immune cells display metabolic plasticity: At rest, they depend mainly on mitochondrial oxidative phosphorylation, but swiftly shift to aerobic glycolysis upon activation to fuel effector functions. Pro‐inflammatory subsets like Th1 cells and M1 macrophages lean heavily on glycolysis, whereas regulatory T cells favour fatty acid oxidation. Central pathways—glycolysis, the tricarboxylic acid (TCA) cycle, and amino acid metabolism—directly shape immune activation and inflammation via intermediates and regulatory enzymes. For example, succinate and itaconic acid are critical in inflammation control, while fatty acid and cholesterol metabolism dictate immune cell fate. In metabolic disorders such as obesity, diabetes, fatty liver disease, and atherosclerosis, immune metabolic reprogramming is the main driver of chronic low‐grade inflammation and tissue injury. During infection, a metabolic tug‐of‐war ensues: Pathogens hijack host metabolism for survival, and the host counters by reprogramming its own metabolism. The idea of “trained immunity” highlights how metabolism–epigenetics crosstalk endows innate immunity with memory‐like capacity. These insights inform therapeutic avenues—modulating metabolic pathways, nutritional interventions, and microbiome targeting—with wide potential. Challenges remain, including the complexity of in vivo networks and the need for precise interventions. Yet advances in single‐cell multi‐omics and metabolic flux analysis will deepen mechanistic understanding and enable breakthroughs in precision strategies.